Differential effects caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney

P. K. Chatterjee, Z. Todorovic, A. Sivarajah, H. Mota-Filipe, Paul Anthony James Brown, Keith Nicol Stewart, S. Cuzzocrea, C. Thiemermann

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Caspase activation has been implicated in the development of ischemia-reperfusion injury. Here, we investigate the effects of different caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. Bilateral clamping of renal pedicles (45 min) followed by reperfusion (6 h) caused significant renal dysfunction and marked renal injury. Caspase-1 inhibitor II (N-acetyl-L-tyrosyl-L-valyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxo-propyl]-L-alaninamide, Ac-YVAD-CMK, 3 mg/kg, administered i.p.) significantly reduced biochemical and histological evidence of renal dysfunction and injury. However, although caspase-3 inhibitor I (N-acetyl-L-aspartyl-L-glutamyl-N-(2-carboxyl-1-formylethyl]-L-valinamide, Ac-DEVD-CHO, 3 mg/kg, administered i.p.) produced a significant improvement of renal (glomerular) dysfunction (reduction of serum creatinine levels), it was not able to reduce tubular dysfunction and injury. Furthermore, the pan-caspase inhibitor caspase inhibitor III (N-tert-butoxycarbonyl-aspartyl(OMe)-fluoromethylketone, Boc-D-FMK, 3 mg/kg, administered i.p.) did not reduce renal dysfunction and injury. Both caspase-1 and -3 inhibitors markedly reduced the evidence of oxidative and nitrosative stress in rat kidneys subjected to ischemia-reperfusion. Overall, these results demonstrate that inhibition of caspase-1 reduces renal ischemia-reperfusion injury to a greater extent than caspase-3 inhibition, supporting the notion that the mode of acute cell death in our model of renal ischemia-reperfusion is primarily via necrosis. Furthermore, our finding that a pan-caspase inhibitor did not reduce the renal dysfunction and injury suggests that activation of some caspases during ischemia reperfusion could provide protection against acute ischemic renal injury. Overall, these results demonstrate that inhibition of caspase-1 activity reduces renal ischemia-reperfusion injury and that this therapeutic strategy may be of benefit against ischemic acute renal failure. (C) 2004 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)173-183
Number of pages10
JournalEuropean Journal of Pharmacology
Volume503
Issue number1-3
DOIs
Publication statusPublished - 2004

Keywords

  • renal/kidney
  • ischemia
  • reperfusion injury
  • caspase
  • caspase inhibitor
  • EPITHELIAL-CELL INJURY
  • ISCHEMIA/REPERFUSION INJURY
  • HEART APOPTOSIS
  • FAILURE
  • DEATH
  • INFLAMMATION
  • PATHOPHYSIOLOGY
  • NECROSIS
  • DAMAGE
  • MODEL

Cite this

Chatterjee, P. K., Todorovic, Z., Sivarajah, A., Mota-Filipe, H., Brown, P. A. J., Stewart, K. N., ... Thiemermann, C. (2004). Differential effects caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. European Journal of Pharmacology, 503(1-3), 173-183. https://doi.org/10.1016/j.ejphar.2004.09.025

Differential effects caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. / Chatterjee, P. K.; Todorovic, Z.; Sivarajah, A.; Mota-Filipe, H.; Brown, Paul Anthony James; Stewart, Keith Nicol; Cuzzocrea, S.; Thiemermann, C.

In: European Journal of Pharmacology, Vol. 503, No. 1-3, 2004, p. 173-183.

Research output: Contribution to journalArticle

Chatterjee, PK, Todorovic, Z, Sivarajah, A, Mota-Filipe, H, Brown, PAJ, Stewart, KN, Cuzzocrea, S & Thiemermann, C 2004, 'Differential effects caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney', European Journal of Pharmacology, vol. 503, no. 1-3, pp. 173-183. https://doi.org/10.1016/j.ejphar.2004.09.025
Chatterjee, P. K. ; Todorovic, Z. ; Sivarajah, A. ; Mota-Filipe, H. ; Brown, Paul Anthony James ; Stewart, Keith Nicol ; Cuzzocrea, S. ; Thiemermann, C. / Differential effects caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. In: European Journal of Pharmacology. 2004 ; Vol. 503, No. 1-3. pp. 173-183.
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AU - Brown, Paul Anthony James

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N2 - Caspase activation has been implicated in the development of ischemia-reperfusion injury. Here, we investigate the effects of different caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. Bilateral clamping of renal pedicles (45 min) followed by reperfusion (6 h) caused significant renal dysfunction and marked renal injury. Caspase-1 inhibitor II (N-acetyl-L-tyrosyl-L-valyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxo-propyl]-L-alaninamide, Ac-YVAD-CMK, 3 mg/kg, administered i.p.) significantly reduced biochemical and histological evidence of renal dysfunction and injury. However, although caspase-3 inhibitor I (N-acetyl-L-aspartyl-L-glutamyl-N-(2-carboxyl-1-formylethyl]-L-valinamide, Ac-DEVD-CHO, 3 mg/kg, administered i.p.) produced a significant improvement of renal (glomerular) dysfunction (reduction of serum creatinine levels), it was not able to reduce tubular dysfunction and injury. Furthermore, the pan-caspase inhibitor caspase inhibitor III (N-tert-butoxycarbonyl-aspartyl(OMe)-fluoromethylketone, Boc-D-FMK, 3 mg/kg, administered i.p.) did not reduce renal dysfunction and injury. Both caspase-1 and -3 inhibitors markedly reduced the evidence of oxidative and nitrosative stress in rat kidneys subjected to ischemia-reperfusion. Overall, these results demonstrate that inhibition of caspase-1 reduces renal ischemia-reperfusion injury to a greater extent than caspase-3 inhibition, supporting the notion that the mode of acute cell death in our model of renal ischemia-reperfusion is primarily via necrosis. Furthermore, our finding that a pan-caspase inhibitor did not reduce the renal dysfunction and injury suggests that activation of some caspases during ischemia reperfusion could provide protection against acute ischemic renal injury. Overall, these results demonstrate that inhibition of caspase-1 activity reduces renal ischemia-reperfusion injury and that this therapeutic strategy may be of benefit against ischemic acute renal failure. (C) 2004 Elsevier B.V. All rights reserved.

AB - Caspase activation has been implicated in the development of ischemia-reperfusion injury. Here, we investigate the effects of different caspase inhibitors on the renal dysfunction and injury caused by ischemia-reperfusion of the rat kidney. Bilateral clamping of renal pedicles (45 min) followed by reperfusion (6 h) caused significant renal dysfunction and marked renal injury. Caspase-1 inhibitor II (N-acetyl-L-tyrosyl-L-valyl-N-[(1S)-1-(carboxymethyl)-3-chloro-2-oxo-propyl]-L-alaninamide, Ac-YVAD-CMK, 3 mg/kg, administered i.p.) significantly reduced biochemical and histological evidence of renal dysfunction and injury. However, although caspase-3 inhibitor I (N-acetyl-L-aspartyl-L-glutamyl-N-(2-carboxyl-1-formylethyl]-L-valinamide, Ac-DEVD-CHO, 3 mg/kg, administered i.p.) produced a significant improvement of renal (glomerular) dysfunction (reduction of serum creatinine levels), it was not able to reduce tubular dysfunction and injury. Furthermore, the pan-caspase inhibitor caspase inhibitor III (N-tert-butoxycarbonyl-aspartyl(OMe)-fluoromethylketone, Boc-D-FMK, 3 mg/kg, administered i.p.) did not reduce renal dysfunction and injury. Both caspase-1 and -3 inhibitors markedly reduced the evidence of oxidative and nitrosative stress in rat kidneys subjected to ischemia-reperfusion. Overall, these results demonstrate that inhibition of caspase-1 reduces renal ischemia-reperfusion injury to a greater extent than caspase-3 inhibition, supporting the notion that the mode of acute cell death in our model of renal ischemia-reperfusion is primarily via necrosis. Furthermore, our finding that a pan-caspase inhibitor did not reduce the renal dysfunction and injury suggests that activation of some caspases during ischemia reperfusion could provide protection against acute ischemic renal injury. Overall, these results demonstrate that inhibition of caspase-1 activity reduces renal ischemia-reperfusion injury and that this therapeutic strategy may be of benefit against ischemic acute renal failure. (C) 2004 Elsevier B.V. All rights reserved.

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KW - reperfusion injury

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KW - caspase inhibitor

KW - EPITHELIAL-CELL INJURY

KW - ISCHEMIA/REPERFUSION INJURY

KW - HEART APOPTOSIS

KW - FAILURE

KW - DEATH

KW - INFLAMMATION

KW - PATHOPHYSIOLOGY

KW - NECROSIS

KW - DAMAGE

KW - MODEL

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DO - 10.1016/j.ejphar.2004.09.025

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